Kadoch Lab Research

BAF Complex Mutations in Cancer and Disease

Recent whole-genome sequencing studies of human cancers have heralded the discovery of several new, surprising classes of genes not previously known to play causal roles in cancer. One of the most significant findings unveiled in these genomic studies is the high mutation frequency in genes involved in epigenomic and chromatin biology-based processes. The most frequent and wide-spread among them are mutations in the genes encoding subunits of the mSWI/SNF (BAF) ATP-dependent chromatin remodeling complexes, which we recently determined to be broadly recurrent in >20% of all human cancers. To investigate the underlying mechanism, we have studied a rare, genomically well-defined cancer type, human synovial sarcoma (SS) in which 100% of tumors have a precise translocation involving a specific subunit, SS18, indicating that the translocation is the initiating oncogenic event. We have expanded this approach to numerous other cancer types with documented BAF mutations, aiming to apply the same biochemistry and genome analysis to understanding these prolific cancer mutations, as well as developmental disorders with similarly well-documented BAF complex mutations.

The central focus of our laboratory is to understand BAF complex pathway-of-assembly, to determine the complex subunit and associated protein factor composition of oncogenic BAF complexes, and to define the mechanistic basis of locus-specific and genome-wide retargeting. These key goals build upon our unique expertise at the border of biochemistry and chromatin regulation, and create for a new synthesis of concepts and methodologies as novel strategies to target a broad range of human cancers.